Racemic betaxolol of formula (2) is a β-adrenoreceptor antagonist with a pharmacological and pharmacokinetic profile for the treatment of chronic cardiovascular diseases like glaucoma. The disease glaucoma is characterized by progressive damage to the optic nerve caused by the increased pressure within the eye. Glaucoma is a serious disease of the eye, which may lead to the loss of peripheral vision and if untreated total blindness.
β-adrenoreceptor antagonist (β-blockers) are popularly used to lower intraoccular tension, other conditions of increased intraoccular pressure and management of essential hypertension. The principle effect of β-adrenoreceptor blocker is to reduce cardiac activity by diminishing or preventing β-adrenoreceptor stimulation i.e. by reducing the rate and force of contraction of the heart.
The processes employed for the preparation of betaxolol in the art involve protecting the phenol functional group so that the alcohol functionality can be alkylated. The resulting protection and deprotection steps extend the length of synthesis.
Manoury et al., (U.S. Pat. No. 4,252,984) describes the preparation of betaxolol which involves the benzylation of the phenolic alcohol of 4-hydroxyphenethanoic acid. The ester group is then reduced to alcohol and then condensation of 2-(4-benzyloxyphenyl)ethanol with cyclopropyl methyl halide to yield cyclopropyl methyl2-(4-benzyloxyphenyl)ether. It is then debenzylated and treated with epichlorohydrin to yield the compound, which on treatment with isopropylamine gives the betaxolol.
In another U.S. Pat. No. 4,760,182 by Ippolito et al., 4-hydroxyphenethanol is converted to a phenoxide anion with a base and then reacting it with epichlorohydrin to yield 1-(4-(2-hydroxyethyl)phenoxy)2,3-epoxypropane.
Wang et al., (U.S. Pat. No. 5,731,463 ) describes selective alkylation of the 4-hydroxy phenethanol via an oxygen dianion to produce intermediate which on reaction with epichlorohydrin and subsequent addition of isopropylamine produces the end product betaxolol.
In all the above processes cyclopropylmethyl halide has been employed for introducing cyclopropyl group as a reactive intermediate. The cyclopropylmethyl halide, is expensive, highly lachrymetric and unstable. These limitations make the reported processes economically unviable and difficult to scale up.
Therefore it is necessary to develop a short, simple, an economically viable alternative process for RS betaxolol wherein the use of cyclopropylmethyl halide is avoided, and steps involving protection and deprotection are avoided.